Macrolide antibiotics are commonly used antibacterial agents. For over four decades, macrolide compounds have been used as safe and effective antibacterial agents against a wide spectrum of bacterial organisms. The macrolide compounds generally demonstrate activity against a wide spectrum of bacterial organisms. Erythromycins A, B, C and D having the formula:
(I)ErythromycinR′R″A—OH—CH3B—H—CH3C—OH—HD—H—Hare well-known and potent antibacterial agents, which have been widely used to treat and prevent bacterial infection. Erythromycin compounds are only a few of the macrocyclic antibacterial agents currently in use in the clinical setting. Clarithromycin, for example, is a 6-O-methylerythromycin A derivative, which has demonstrated antibacterial activity against a broad spectrum of bacterial organisms. See, for example, U.S. Pat. No. 4,331,803. Another common anti-infective agent, azithromycin, differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring.
The extensive clinical application of these antibiotic agents has resulted in an increasing emergence of macrolide-resistant strains of bacteria. The medical need for effective agents against resistant organisms, including staphylococci, streptococci and enterococci, has grown as a result of the ever-increasing resistance of the organisms. See, Journal of Antimicrobial Chemotherapy 39, Suppl. A, 1-6 (1997) and Clinical Infectious Diseases 26: 1204-14 (1998).
Ongoing efforts to develop compounds demonstrating activity against the resistant organisms have resulted in a number of new macrolide series. The compounds have been described in the following U.S. patents.
U.S. Pat. No. 5,523,399 describes a class of 5-desosaminylerythronolide derivatives, wherein a carbamoyl group is introduced into the 3-position of the lactone ring. See also U.S. Pat. No. 5,631,355, disclosing 5-desosaminylerythronolide derivatives having a 9,11-bridged cyclic imine group. There is no report of antibacterial activity against a methicillin-resistant strain of Staphylococcus aureus (MRSA).
U.S. Pat. No. 5,770,579 describes a class of 6-O- methylerythromycin, 9-oxime derivatives having antibacterial activity. No activity against MRSA was reported. See also European Patent Publication No. 0 680 967 A1 and French Publication No. 2,732,032 A1.
PCT International Application No. PCT/IB98/00741 relates to a class of 6-O-methyl-9-oxime ketolides which are useful for the treatment of bacterial and protozoal infections. There is no description that the compounds demonstrate activity in inhibiting the bacterial activity of MRSA.
In Chem. Pharm. Bull. 42(5), 1088-1095, 1994, 6-O- methylerythromycin 9-O-substituted oxime derivatives exhibiting activity against erythromycin-resistant Staph. aureus was described. There is no report of antibacterial activity against the MRSA.
The cited compounds are erythromycin derivatives or ketolide derivatives, i.e. wherein the cladinose sugar of the erythromycin is removed. None of the previously cited compounds have a substituent in the 6-O-position other than methyl. U.S. patent application Ser. No. 08/841,038 and U.S. Pat. No. 5,866,549 describe 6-O-substituted erythromycin and ketolide derivatives, respectively, wherein the 6-O-substituent can be other than methyl. Although 9-oxime groups on the 6-O-substituted ketolides was disclosed in U.S. Pat. No. 5,866,549, no activity against MRSA was reported.
The 9-oxime derivatives of erythromycin generally have been described as intermediates for the preparation of macrolide compounds currently in clinical use. However, there has been some recognition that 9-oxime derivatives of erythromycin can have antibacterial activity; see for example U.S. Pat. No. 5,770,579; European Patent Publication No. 0 680 967 A1; French Publication No. 2,732,032 A1; and PCT International Application No. PCT/IB98/00741. There is no recognition or appreciation that macrolide compounds can demonstrate activity against methicillin-resistant strains of staphylococci or that administering a macrolide compound can treat a bacterial infection caused by such MRSA.
Accordingly, there remains a need to identify and develop new classes of macrocylic compounds demonstrating antibacterial activity against an increasing number of multi-drug, methicillin-resistant strains of bacteria. The new classes of macrocyclic compounds can be erythromycin derivatives or ketolide derivatives. A useful drug would demonstrate activity against multi-drug resistant strains of bacteria, in particular MRSA.